Palonosetron, 2-(1-azabicyclo-[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one (Compound A), has the following structural formula, which demonstrates that the compound has two chiral centers. The most active palonosetron isomer has both chiral centers in the S-configuration.

Palonosetron hydrochloride is marketed as ALOXI® and is a selective 5-HT3 receptor antagonist developed for the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV) caused by moderately emetogenic chemotherapy. Palonosetron hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on Jul. 25, 2003, and was commercially launched in September 2003. Palonosetron hydrochloride also is used for treating emesis, which is a gastrointestinal disorder treatable with prokinetic agents, and for treating patients recovering from surgical anesthesia or undergoing a drug therapy whenever a significant side effect is emesis. The recommended dosage of palonosetron is 0.25 mg, which is administered as a single dose about 30 minutes before starting chemotherapy.
The synthetic route for preparing palonosetron is described in U.S. Pat. No. 5,202,333, wherein 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (Compound II) is reacted with (S)-3-amino-1-azabicyclo[2.2.2]octane (Compound III) to obtain (S)—N-(1-azabicyclo-[2.2.2]oct-3-yl)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide (Compound IV), which is recrystallized from a mixture of ethyl acetate and hexane. Reaction of Compound IV with n-butyl lithium in hexane in presence of dimethylformamide (DMF) affords (S)-2-(1-azabicyclo-[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one (Compound V), and treatment of Compound V using palladium hydroxide on carbon with hydrogen affords a diastereomeric mixture containing 98.9% of Compound A. This process is depicted in Scheme 1 below.

U.S. Pat. No. 5,510,486 (the '486 patent) discloses other processes for preparing palonosetron, the pharmaceutically acceptable hydrochloride salt, individual stereoisomers, and mixture of stereoisomers thereof, as illustrated in Scheme 2 below.

According to Route A, 1,2,3,4-tetrahydronaphthalene (Compound VI) is converted into 1,2,3,4-tetrahydro-1-naphthoic acid (Compound VII), which is optically resolved to obtain the S-enantiomer (Compound VIIA). The optically enriched acid then is reacted with thionyl chloride to afford (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride (Compound VIIIA). This acid chloride is reacted with Compound III to afford N-(1-azabicyclo[2.2.2]oct-3S-yl)-(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine (Compound IXA), which subsequently is converted to palonosetron hydrochloride over several steps.
According to Route B, 1,2,3,4-tetrahydro-1-naphthoic acid chloride (Compound VIII) is reacted with Compound III to give N-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarboxamide (Compound IX). The amide then is reduced to give (1-azabicyclo[2.2.2]oct-3S-yl)-(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine (Compound X). The resulting amine is reacted with a formylating agent, then treated with a Lewis acid to afford 2-(1-azabicyclo[2.2.2]oct-S-yl)-2,3,aS,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one as a diastereomeric mixture. This diastereomeric mixture is separated into individual stereoisomers or mixtures of stereoisomers with the desired stereomer, then converted to the hydrochloride salt of palonosetron. The '486 patent (in example 6) discloses a melting point of 303° C. and [α]D=90° (c=1, chloroform). However, based on the previous data, this may be a typographical error and the optical rotation apparently should be [α]D=−90° for the obtained palonosetron hydrochloride.
U.S. Pat. No. 5,567,818 discloses other processes for preparing palonosetron, palonosetron hydrochloride, individual stereoisomers thereof, and mixtures of stereoisomers thereof (Scheme 3).

The starting material 1,8-naphthalenic anhydride is reacted with (S)-1-azabicyclo[2.2.2]-oct-3-ylamine in isopropanol to obtain (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydro-1H-benz[de]isoquinolin-1,3-dione, which is purified by flash chromatography, in step 1 of Scheme 3. In step 2, the product is reduced under hydrogen atmosphere to obtain 2-(1-azabicyclo[2.2.2]oct-3S-yl)-3-hydroxy-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one as a foam. In step 3, the product of step 2 is treated under acidic conditions to provide the dehydration product (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one hydrochloride. In step 4, the dehydration product is hydrogenated to obtain a 7:3 mixture of diastereomers of palonosetron hydrochloride (70% of 2-(1-azabicyclo-[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one and 30% of 2-(1-azabicyclo-[2.2.2]oct-3S-yl)-2,3,3aR,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one). Selective precipitation afforded 97% of the preferred stereoisomer, Compound A, and 3% of the less preferred isomer, Compound B, (2-(1-azabicyclo-[2.2.2]oct-3S-yl)-2,3,3aR,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one). The diastereomeric mixture of 97% Compound A and 3% Compound B was further purified via recrystallization to obtain 99.1% Compound A, with a melting point of 303° C. and [α]D=−90.4° (c=1, chloroform)

In an alternative process, the compound 2-(1-azabicyclo-[2.2.2]oct-3S-yl)-3-hydroxy-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one is obtained via the intermediate 2-oxa-2,4,5,6-tetrahydrobenz[de]naphthal-1-one, as demonstrated in steps 1a-3a of Scheme 3, above.
Usually, the minimal purity of a drug, as mandated by the appropriate regional or national regulative authorities (e.g., the FDA) is at least 99.5%. However, the purity and composition A/B isomer ratio in which the palonosetron hydrochloride is obtained are relatively low (i.e., 99.1% and 97/3, respectively).
Therefore a need still exists in the art for methods of preparing palonosetron and salts thereof, which can be obtained in a single crystallization having higher purity and A/B isomer ratio, which meet the regulatory standards of the various regulating agencies.